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Dual action antibiotics

A compound and group technology, applied in the field of dual-action antibiotics, can solve problems such as no bactericidal effect, low safety limit, and emergence of drug resistance

Inactive Publication Date: 2009-03-11
MORPHOCHEN AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The only option is to use oxazolidinones, but these compounds have no bactericidal effect and their safety margins are quite low
Furthermore, even with these drugs, resistance has emerged in clinical practice

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0089] Example 1: 7-(4-{4-[5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenyl}-piperazin-1-yl )-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid

[0090]

[0091] 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid boron diacetate (7-chloro-1-cyclopropyl-6-fluoro -4-oxo-1,4-dihydro-quinoline-3-carboxylateboron diacetate) (described in WO8807998; 103mg, 0.25mmol), N-[3-(3-fluoro-4-piperazin-1-yl-benzene base)-2-oxo-oxazolidinone-5-ylmethyl]acetamide (described in J.Med Chem1996,39,673-679 and US5547950; 100mg, 0.3mmol) and N,N'-dimethyl A mixture of p-toluidine (0.054ml, 0.375mmol) was stirred in 0.5ml of 1-methyl-2-pyrrolidone at 120°C for 12 hours. The reaction mixture was poured into water, and the resulting crystals were collected by filtration and purified by silica gel chromatography. Fractions of interest were pooled to yield 38 mg (26%) of beige material.

[0092] C 29 h 29 f 2 N 5 o 6 (581.5812)

[0...

Embodiment 2

[0095] Example 2: 9-(4-{4-[5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenyl}-piperazin-1-yl )-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3a-aza-phenalene-5-carboxylic acid:

[0096]

[0097] 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido-[1,2,3-des]-1,4-benzoxazine-6- Carboxylic acid (commercially available from Aldrich (47267-0), described in Chem. Pharm. Bull. 1987, 35, 1896-1902, 84 mg; 0.3 mmol), N-[3-(3-fluoro-4-piper Oxazin-1-yl-phenyl)-2-oxo-oxazolidinon-5-ylmethyl]acetamide (described in J. Med Chem 1996, 39, 673-9 and US5547950; 121 mg, 0.36 mmol) and A suspension of DABCO (43.7mg, 0.39mmol) in acetonitrile / water (7ml, 2:1) was refluxed for 12 days. The acetonitrile was removed alkaline and the residue was poured into water. The crystals were collected by filtration and further stirred in methanol (5 ml). The resulting crystals were recrystallized in DMF / water (4:1) to obtain 95 mg of a beige substance (53%).

[0098] C 29 h 29 f 2 N 5 o...

Embodiment 3

[0101] Example 3: 7-((3R,S)-3-{4-[(5S)-5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro- Phenylcarbamoyl}-piperazin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid

[0102]

[0103] 2([(5S)-5-(Acetamidomethyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenylcarbamoyl)-piperazine-1,4-dicarboxylic acid Di-tert-butyl ester

[0104] Add 0.210ml of phosphorus oxychloride (phosphoroxychloride) at -15°C to 0.4g of N[(5S)-3-(4-amino-3-fluoro-phenyl)-2-oxo-oxazolidine in 10ml of pyridine -5-ylmethyl]acetamide (1.5mmol) and 0.545g piperazine-1,2,4-tricarboxylic acid 1-4-di-tert-butyl ester (1.65mmol). The reaction was monitored by TLC. The reaction mixture was poured onto ice, diluted with dichloromethane, the organic layer was washed with water and brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified by chromatography using dichloromethane / methanol 95 / 5 as eluent to give a colorless foam.

[0105] Yield: 0.390 g, 45%, C ...

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PUM

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Abstract

The present invention relates to compounds of the Formula I that are useful antimicrobial agents and effective against a variety of multi-drug resistant bacteria.

Description

[0001] This application is a divisional application of the Chinese patent application 02819724.0 filed on October 4, 2002, and the invention title is "Dual Action Antibiotics". technical field [0002] The present invention describes novel compounds and antibacterial pharmaceutical compositions containing these compounds in which quinolone and oxazolidinone pharmacophores are chemically linked via a linker group which is stable under physiological conditions. These dual-action compounds are useful antimicrobial agents that are effective against a variety of human and animal pathogens, including Gram-positive aerobic bacteria such as multidrug-resistant staphylococci, streptococci, and enterococci, as well as Gram Negative bacteria such as Moraxella catarrhalis and Haemophilius influenza, and anaerobic microorganisms such as Bacteroides spp. and Clostridia spp., and anti- Acid microorganisms such as Mycobacterium tuberculosis, Mycobacterium avium spp. Background technique ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/14C07D413/12C07D498/04C07D471/04A61K31/496A61P31/04A61K31/5383C07D498/06
CPCC07D471/04C07D413/14C07D413/12A61P31/00A61P31/04A61P9/00
Inventor 克里斯蒂安·胡布施韦尔朗让-吕克·施佩克林
Owner MORPHOCHEN AG
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